Stereospecific total steroidal synthesis via substituted C/D-trans indanones

ABSTRACT

and lower alkyl; R7 is lower alkyl; R15 is selected from the group consisting of oxo, lower alkylenedioxy or (hydrogen and lower alkoxy); B is selected from the group consisting of lower alkoxy-carbonyl-methylene, lower-aryloxy-carbonyl-methylene, cyanomethylene, lower alkyl sulfinyl-methylene, lower alkyl sulfonyl-methylene, and R25 and R26 are independently selected from the group consisting of hydrogen, hydroxyl and lower alkyl.   wherein R6 is selected from the group consisting of   WHEREIN M IS AN INTEGER HAVING A VALUE OF 1 OR 2; R4 is hydrogen or lower alkyl; Z is lower alkylenedioxy, CH(OR2) and carbonyl; R8 when taken alone is hydrogen; R9 when taken alone is lower alkoxycarbonyl, aryloxy-carbonyl, lower cycloalkyloxycarbonyl, carbonyl-halide, hydrogen, carboxy, formyl and methylene-X, where X is a leaving group and when taken together are methylene; with the proviso that when Z is carbonyl R8 when taken alone is hydrogen; R9 when taken alone is carbonyl halide, hydrogen, carboxy, formyl and methylene-X where X is a leaving group and when taken together are methylene and R2 is hydrogen, lower alkyl, lower alkoxy-lower alkyl, phenyl-lower alkyl, tetrahydropyranyl, lower alkanoyl, benzoyl, nitrobenzoyl, carboxy-lower alkanoyl, carboxybenzoyl, trifluoroacetyl and camphorsulfonyl AND REACTING THEM IN THE CASE WHERE R8 and R9 taken together are methylene or R8 is hydrogen and R9 is methylene-X with Beta keto esters and other analogs of the formula   Total synthesis of known progestationally active steroidal materials. The steroids can be synthesized depending on the particular starting reactants selected by employing as intermediates bicyclic compounds of the formula

United States Patent [:91

Hajos l l STEREOSPECIFIC TOTAL STEROIDAL SYNTHESIS VIA SUBSTITUTED C/D-TRANS INDANONES [75] lnventor: Zoltan George Hajos, Upper Montclair, NJ

[73] Assignee: Hoffmann-La Roche Inc., Nutley,

22 Filed: June 24, 1974 211 Appl. No; 482,822

Related US. Application Data {62} Division of 56]. No. 765,023, on. 4, l968.

[52] US. Cl. .6 260/586 F; 260/3403; 260/3405; 260/3459; 260/456 R; 260/471 R; 260/475 R; 260/476 C; 260/485.2; 260/487; 260/488 [51 I Int. CL i i ..C07C 49/36; C07C 49/38; C07C 49/27; C07C 43/18 [58] Field of Search ii 260/586 E, 586 F, 340.3,

260/3405, 345.9, 456 R, 471 R, 475 R, 476 C, 485 L, 487, 488 B, 590 C {56] References Cited UNITED STATES PATENTS 3.021227 2/1962 Atwater i 260/586 E X 3,080,380 3/1963 Atwaterw 260/586 E X 3,658,847 4/1972 Fried i, 260/586 F X 3.816.458 6/1974 Saucy 260/586 FX Primary Examiner-Norman Morgenstern Attorney, Agent, or Firm-Samuel L. Welt; Jon S. Saxe; George M. Gould Dec. 9, 1975 wherein m is an integer having a value of l or 2; R is hydrogen or lower alkyl; Z is lower alkylenedioxy, CH(OR and carbonyl; R when taken alone is hydrogen; R when taken alone is lower all-toxycarbonyl, aryloxy-earbonyl, lower cycloalkyloxycarbonyl, carbonyl-halide. hydrogen, carboxy, formyl and methylene-X, where X is a leaving group and when taken together are methylene; with the proviso that when Z is carbonyl R when taken alone is hydrogen; R when taken alone is carbonyl halide, hydrogen, carboxy, formyl and methylene-X where X is 21 leaving group and when taken together are methylene and R is hydrogen, lower alkyl, lower alkoxy-lower alkyl, phenyl-lower alkyl. tetrahydropyranyl. lower alkanoyl. benzoyl, nitrobenzoyl, carhoxydower alkanoyl, carboxybenzoyl, trifluoroacetyl and camphorsulfonyl and reacting them in the case where R and R taken together are methylene or R is hydrogen and R is methylene-X with B-keto esters and other analogs of the formula wherein R is selected from the group consisting of and lower alkyl; R, is lower alkyl; R is selected from the group consisting of oxo, lower alkylenedioxy or (hydrogen and lower alkoxy); B is selected from the group consisting of lower alkoxy-carbonyl-methylene, lower-aryloxy-carbonyl-methylene, cyanomethylene, lower alkyl sulfinyLmethylene, lower alkyl sulfonyl-methylene, and R and R are independently selected from the group consisting of hydrogen, hydroxyl and lower alkyl.

4 Claims, N0 Drawings STEREOSPECIFIC TOTAL STEROIDAL SYNTHESIS VIA SUBSTITUTED C/D-TRANS INDANONES This is a division of application Ser. No. 765,023, 5

filed Oct. 4, 1968.

BACKGROUND OF THE INVENTION SUMMARY OF THE INVENTION In one aspect, this invention relates to a process for preparing intermediates useful in the preparation of tricyclic compounds of the formula where R is hydrogen or lower alkyl; R, is hydrogen or lower alkyl; Z is defined hereinafter; m is an integer having the value of l or 2. Another aspect of this invention relates to a process for preparing intermediates which enable the direct preparation of steroids of the formulae and wherein R R and m are as defined above; Z is defined hereinafter; R is hydrogen or lower alkyl and R and R are independently selected from the group consisting of lower alkyl, hydrogen and hydroxyl.

In accordance with this invention, it has been discovered that compounds of the formulae 1, [l and Ill above, can be synthesized depending on the particular starting 0 reactants selected by employing as intermediates bicyclic compounds of the formula m is an integer having a value of 1 or 2; R is hydrogen or lower alkyl; 2 is lower alkylenedioxy, CI-I(OR and carbonyl; R when taken alone is hydrogen; R when taken alone is lower alkoxycarbonyl, aryloxy-carbonyl, lower cycloalkyloxycarbonyl, carbonyl-halide, hydrogen, carboxy, formyl and methylene-X, where X is a leaving group and when taken together are methylene; with the proviso that when Z is carbonyl, R when taken alone is hydrogen; R when taken alone is carbonyl halide, hydrogen, carboxy, formyl and methylene-X where X is a leaving group and when taken together are methylene and R is hydrogen, lower alkyl, lower alkoxy-lower alkyl, phenyl-lower alkyl, tetrahydropyranyl, lower alkanoyl, benzoyl, nitrobenzoyl, carboxy-lower alkanoyl, carboxybenzoyl,

III

trifluoroacety and camphorsulfonyl and reacting them in the case where R and R taken together are methylene or R is hydrogen and R is methylene-X with B-keto esters and other analogs of the formula wherein R is selected from the group consisting of and lower alkyl; R is lower alkyl; R is selected from the group consisting of oxo, lower alkylenedioxy or (hydrogen and lower alkoxy); B is selected from the group consisting of lower alkoxy-carbonyl-methylene, lower-aryloxy-carbonyl-methylene, cyanomethylene, lower alkyl sulfinyl-methylene, lower alkyl sulfonyl-methylene, and R and R are independently selected from the group consisting of hydrogen, hydroxyl and lower alkyl.

In still another aspect, this invention relates to the preparation of the compounds of formula 111 above wherein R is hydrogen, by reacting the compounds of formulae lV-a and lV-c with a vinylogous cyclic-betaketo compound of the formula:

wherein B is selected from the group consisting of lower alkoxy carbonyl-methylene, lower aryloxy carbonylmethylene, lower alkyl sulfinyl-methylene and lower alkyl sulfonyl-rnethylene. Structure Ill can also be obtained starting with a compound of the formula V, in which R has been chosen to be oxo by reaction with compounds of the formulae lV-a and lV-c.

A further aspect of this invention relates to novel intermediates of the formula IV. Subgeneric to the bicyclic compound of formula IV above are compounds of the formulae:

2% l5 IV 1'1 l CHO I IV (0) I I l l H 30 CH R i Z IV (a) I i I H COZR (ai IV o I I H CODE wherein R Z, in and X are as defined aforesaid; Y is selected from the group consisting of fluorine, chlorine, bromine and iodine and Rs is selected from the group consisting of lower alkyl, lower cycloalkyl and aryl.

DETAILED DESCRIPTION OF THE INVENTION In one aspect, this invention is concerned with novel indanones of the formulae IV, IV-a, IV-b, IV-c, lV-d, IV-e and IV-f which are useful as chemical intermediates as described herein. Also, certain of the keto compounds of formula V are novel and are also considered within the scope of this invention. For purposes of convenience, the rings in formulae I and IV have been numbered. Throughout this specification, in the formulae of compounds containing asymmetric centers or in the designation of such compounds by chemical nomenclature, the desired enantiomeric form is shown or designated. However, unless explicitly indicated otherwise, such illustration and designation should be taken as comprehending the enantiomer shown or designated, as well as its optical antipode or their corresponding racemate. In the formulae presented herein, the various substituents on cyclic compounds are joined to the cyclic nucleus by one of two notations, a solid line indicating a substituent which is in the B-orientation (i.e., above the plane of the paper), or a dotted line indicating a substituent which is in the a-orientation (below the plane of the paper).

As used herein, the term lower alkyl comprehends both side and branched chain hydrocarbon moieties such as methyl, ethyl, isopropyl, n-propyl, t-butyl and the like, having I to 7 carbon atoms in the chain. The preferred compounds are those derivatives wherein R is methyl, ethyl and propyl which can be converted into steroids which exhibit exceptionally active pharmacological properties as hereinafter described. The formative lower-lakyl when used in expressions such as lower alkoxy-lower alkyl have the same significance. Thus, exemplary of the expression lower alkoxy-lower alkyl is a-ethoxy-ethyl and 3-propoxy-propyl. Exemplary of lower alkanoyl are acetyl and propionyl or other residues derived from lower alkane carboxylic acids of l to 6 carbon atoms; lower alkylenedioxy is understood to mean alkylene of l to 6 carbon atoms exemplary of which is ethylenedioxy. The term nitrobenzoyl as used herein comprehends benzo moieties containing one or more aromatic nitrile substituents, for example, nitrobenzoyl moieties such as 4-nitrobenzoyl and dinitrobenzoyl moieties such as 3,5-dinitrobenzoyl. The expression carboxy-lower alkanoyl comprehends clibasic aliphatic acids of l to 7 carbon atoms absent one OH moiety. Similarly, the expression carboxy-benzoyl denotes, for example, phthalic acids absent one OH moiety. The expression halide" or halogen" comprehends chlorine, fluorine, bromine and iodine. The expression lower alkoxy as utilized herein designates a lower alkyl ether group such as methoxy, ethoxy and the like, wherein the alkyl group is as defined above. The term lower alkoxy carbonyl methylene" includes for example, ethoxy carbonylmethylene. The term lower aryloxy carbonyl methylene includes for example, phenyloxy carbonyl methylene. The term aryl" comprehends phenyl or phenyl having one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, nitro, amine and halogen. The expression lower alkylaryl" comprehends, for ex ample, tolyl and ethylphenyl. The term cycloalkyl includes rings containing from 1 to 6 atoms, for example, cycloalkyl and cyclopentyl. Especially preferred compounds of formula IV are those wherein Z" is lower alkoxy, especially t-butoxy although the other derivatives defined hereinabove such as, tetrahydropyranyloxy can be suitably employed in accordance with the process of this invention.

The following schematic flow sheet entitled Reaction Scheme A, exemplifies the process routes employed in accordance with the teachings of this invention for preparation via process routed (l), (2), (3), (4), (5), (6), (7), (8), (9) and (ID), the key intermediates of the formulae IV-c and IV-a, each of which can independently be reacted with the B-keto esters and other analogs thereof of formula V to yield the endproducts of formulae 1, II and III as hereinafter detailed.

Thus, in one aspect of the process of this invention, comprises preparing compounds of the formula IV-a by the general reaction steps l (2) and (4) of Reaction Scheme A to which the numerals and letters in parenthesis are referenced in the following descriptions.

Many of the indanene starting reactants of formula VII wherein Z is carbonyl are known. They may be conveniently synthesized by methods known in the art, for example, by the Michael Addition of methyLvinylketone to 2-lower alkyl-cyclopentane-l,3-dione. The cyclization can be effected using pyrrolidine in a benzene solvent under reflux reaction conditions (cf., U.S. Pat. No. 3,321,488). If desired, other derivatives of formula VII may be prepared. For example, in order to prepare the derivatives wherein Z is hydroxy, the corresponding oxo group can be selectively reduced with lithium aluminum tri-(lower alkoxy)-hydride or sodium borohydride at low temperatures. Derivatives wherein Z is lower alkoxy, for example, tertiarybutoxy, can be obtained from the corresponding hydroxy derivative by reaction under acid conditions with isobutylene by means known in the art. l-Carboxy-lower alkanoyl derivatives of formula VII can be conveniently obtained by reacting dibasic lower alkanoic acids such as, succinic acid and phthalic acid and the like, with corresponding compounds containing the hydroxy-methylene moiety. Other derivatives in accordance with the 5 definition of Z can be obtained by methods known to those skilled in the art.

LII

REACT ION SCHEME A l Hglm (CH2lm COOH V lll R EACT ION SCHEMLA-continued H lm JLLLLLG.

o l [12) I l COOH - i IV I H COY Hz m i ii i CH2X wherein R Z, m R' X and Y are as defined aforesaid.

The bicyclic ketone of formula VII can be converted to acid compounds of formula Vlll by reaction in accordance with Step (1) of Reaction Scheme A with a base sufficiently strong to afford the corresponding anion of the bicyclic compound via conjugate enolate formation. Exemplary of the suitable bases for this reaction are alkali metal amides such as sodium amide and the like; alkali metal alkoxides such as lithium methoxide and the like and alkali metal hydrides such as sodium hydride. Generally, it is preferred to conduct this reaction at room temperature although temperatures from about -40C. to the boiling point of the reaction mixture can be utilized. The reaction is conve niently carried out in liquid ammonia or in the presence of an organic solvent inert to the reactants such as dimethylsulfoxide, dimethylformamide; hydrocarbons, e.g., benzene and toluene; and ethers, e.g., diethylether and tetrahydrofuran. A preferred solvent for this reaction is dimethylsulfoxide. This intermediate enolate bicyclic reaction product can be isolated by conventional techniques such as, for example, by removal of the solvent using vacuum distillation.

lV-f

R J l\ (CH2 m I H ca;

The anion which is thus obtained as a residue can be carboxylated by reaction with excess carbon dioxide to afford the 4-indane carbocyclic acid of the formula VIII. The carboxylation can be suitably effected by employing solid carbon dioxide in the form of dry ice or passing gaseous carbon dioxide into the reaction medium. Exemplary of the desirable solvents for this reaction are any of the aforementioned listed solvents which can be employed to prepare the anion with the exception of liquid ammonia, which is basic and dimethylsulfoxide, which tends to promote decarboxylation. In cases wherein liquid ammonia or dimethylsulfoxide is employed to prepare the anion, an inert solvent should be substituted when conducting the carbonation reaction. Suitable reaction temperatures are in the range of -C and about 40C. A preferred operating temperature range is 15C-25C. Separation of the desired reaction product from the reaction medium can be effected by extraction. The extraction is suitably conducted in a hydrocarbon solvent in the presence of a dilute base such as sodium hydroxide of lithium carbonate to form the corresponding water soluble salt of the acid. Base extraction is employed so as to remove the desired product from the starting material. The aqueous layer is separated and carefully acidified to a pH of between 2.5 and 4.5 with dilute mineral acid and the desired product is then obtained by conventional techniques. Although the reaction can be suitably conducted at atmospheric pressure, increased yields can be obtained by conducting the reaction under higher pressures, e.g., in the range of 450 to 550 psi. Carboxylation takes place only at C -4 position on the indane nucleus in agreement with the preference for heteroannular conjugate anion formation with compound VII.

Inasmuch as the ultimate goal of this invention is to produce a compound of the formula I containing a 9baconfiguration, it is clear that the hydrogenation of the compound of formula VI]! in accordance with Step (2) of Reaction Scheme A must predominantly proceed so as to yield a trans-hydrogenation product with respect to the two rings of the S-indanone or the corresponding 2-napthalenone compounds. A feature of this invention is that the desired hydrogenation to yield a transfused bicyclic structure can be effected in extremely high yields. The hydrogenation is conducted in the presence of a catalyst preferably a noble metal catalyst, such as palladium, rhodium, irridium, platinum and the like. Especially preferred is the palladium catalyst. The noble metal catalyst can be utilized with or without a carrier and if a carrier is used, conventional carriers are suitable. It is preferred to use palladium on barium or calcium sulfate. Especially preferred is 10 per cent Pd/BaSO The ratio of catalyst to substrate is not critical and can be varied. However, it has been found advantageous to use a weight ratio of catalyst to substrate from about 1:1 to about l:lO. Especially preferred is a ratio of 1:3. The hydrogenation is suitably effected in the presence of an inert organic solvent for the particular compound of formula VI] being hydrogenated, for example, a lower alkanol, such as methanol, isopropano] or octanol; ketones for example, lower alkyl ke tones such as acetone or methylethyl ketone; lower alkyl esters of lower alkanoic acids such as ethyl acetate; lower alkyl ethers such as diethyl ether to tetrahydrofuran; aromatic hydrocarbons such as toluene or benzene and the like. It is especially preferred to conduct the hydrogenation using a lower alkanol as the solvent and it is preferably conducted under non-acidic conditions. Suitably, the hydrogenation is conducted under neutral conditions. It can be conducted at atmospheric pressure or below or above atmospheric pressure, for example, at pressures of as high as about 50 atmosphere. Also, the hydrogenation can be conducted at room temperature or temperatures above or below room temperature. As a matter of convenience, it is preferred to conduct the hydrogenation at room temperature. The hydrogenation is effected by utilizing conventional techniques, for example, the hydrogenation should be stopped after the uptake of the equivalent of hydrogen or if the absorption of hydrogen ceases before the uptake of an equivalent of hydrogen, it is advantageous to then add more catalyst and further hydrogenate. It will be appreciated that another significant aspect of this hydrogenation step lies in that the hydrogenation of the compound of formula Vlll to afford the compound of formula lV-f proceeds without substantial decarboxylation of the substituted indane of formula Vlll. Depending on the hydrogenation conditions used, the group represented by Z in formula VII! can be modified during the hydrogenation. For example, under the above-described hydrogenation condi- 10 tions. when Z is CR and R is a group such as alkoxylower alkyl or tetrahydropyranyl, such group can be split off during the hydrogenation procedure. A preferred group for R in which to conduct the hydrogenation and many of the subsequent other reactions is alkyl, especially, t-butyl.

The thus obtained saturated compound of formula lV-f can be converted to the 4-methylene-trans-fused compounds of formula IV-a by employing a modified Mannich-type reaction in accordance with Step (4) of Reaction Scheme A. The conversion can be effected using formaldehyde in the presence of a primary or secondary amine salts. Suitable salts which may be employed are those derived from strong mineral or organic acids such as for example, hydrogen halides, preferably as the chloride, sulfuric acid, oxalic acid and the like, such as for example, piperidine hydrochloride. The reaction can be suitably carried out at a temperature range of from 0C to about C. A preferred temperature range for this reaction is l5C-40C. While the ratio of reactants used for the reaction is not critical, it has been found advantageous to use approximately a l0:l molar ratio of formaldehyde to keto acid and a (ll :l to I21 molar ratio of amine to keto acid.

The reaction is best effected in a dimethylsulfoxide solvent which functions both as a solvent for the reaction and also as a decarboxylating agent. Most advantageous results are obtained by allowing the compound of formula IV-f to decarboxylate in the dimethylsulfoxide solvent so as to form the corresponding anion and quench it immediately with the Mannich System formed by the addition of formaldehyde and primary or secondary amine salt. Aqueous formalin (37 per cent 40 per cent) is a generally satisfactory source of formaldehyde for this reaction. Exemplary of the amines suitable for this reaction include heterocyclic amines such as morpholine, piperidine and pyrrolidine; monoamines such as methylamine, butylamine and benzylamine. An especially preferred amine for this reaction is piperidine. Other polar solvents such as, for example, dimethylformamide and hexamethylphosphoramide which are inert to the reactants may be employed in conjunction with the dimethylsulfoxide. The dimethylsulfoxide solvent promotes decarboxylation and anion formation at the bicyclic C-4 position notwithstanding the known preferential tendency of these compounds to enolize in the direction of the bicyclic 06 position.

In another aspect of this invention in accordance with Reaction Scheme A, compounds of Formula lV-c may be prepared by alternate process routes (3%9), (5 7 9), (5 l0) and (5- 6 8).

Thus, the compounds of formula lV-e can be pre pared in accordance with Step (5) from the B-keto acids of formula lV-f in excellent yields employing an organic or inorganic acyl halide preferably thionyl halide, e.g., thionyl chloride; phosphorous trihalide, preferably phosphorous trichloride and phosphorous pentahalide, preferably phosphorous pentachloride. Thionyl chloride is particularly convenient since the by products formed are gases and can be easily separated from the acid chloride. Any excess of the low boiling thionyl chloride can be easily removed by distillation. This substitution reaction was successfully effected notwithstanding the known prior art [ef., C. B. Hurd et al., J. Am. Chem. Soc. 62, 1548, (1940)} which teaches the inability to prepare B-keto acyl halides by conventional reaction techniques from the correspond ing ,B-keto acids. The reaction is suitably conducted at 1 l a temperature of from C to the boiling point of the solvent. Suitable solvents for the conversion are thionyl chloride (neat) or in an inert organic solvent such as. for example, benzene, toluene. hexane, cyclohexane and the like.

4-Carbonyl halide indanone compounds of formula We, can be converted to the corresponding esters of formula lV-d by means known in the art. Preferred esters are those wherein R;, is lower alkyl, especially methyl and ethyl. The esters can be conveniently obtained by reacting the halide with an alkali alkoxide, e.g., sodium methoxide in a solvent such as, for example, lower alcohol, e.g., methanol and the like. Alternatively, the esters of formula lV-d may be obtained by reacting the halide with carbonyl diimidazolide in tetra hydrofuran solvent, then further reacting the thus obtained product with the desired aliphatic or aryl alcohol, e.g., phenol, methanol, ethanol and the like at room temperature to the reflux temperature of the solvent in, for example, tetrahydrofuran to obtain the desired ester.

As a further alternate wherein it is desired to prepare 4-alkoxy carbonyl indanones of formula lV-d, the con version can be effected by treatment of the acids of formula lV-f with an ethereal solution of a diazoalkane such as diazomethane by known means. The reagent is a yellow gas and small quantities can be prepared conveniently prior to use in the form of a solution in ether. When the yellow ethereal solution is added in portions to a solution or suspension of the acid in ether at room temperature, nitrogen is evolved at once and the yellow color is discharged. When the yellow color persists, which is an indication that excess diazomethane has been added, the solution can be heated, e.g., on a stream bath to expel excess reagent. Since the only byproduct is a gas, a solution of the desired ester in ether results.

The esters of formula lVd can also be prepared by first esterifying the unsaturated acid compounds of formula Vlll to compounds of formula Vlll-a in accordance with Reaction Scheme A by the aforementioned methods and then catalytically hydrogenating this unsaturated ester. The steric course of this hydrogenation proceeds so as to yield the C/D-trans-hydrogenated product. Thus, an identical product of the structure of formula lV-d with C/D-trans-ring fusion is obtained in a similar manner to the case wherein the acid of formula VIII is employed directly as the starting reactant for the hydrogenation step. The bicyclic CID-transstructure obtained by the catalytic hydrogenation of the ester may be explained (although applicant is not bound by this theory) by postulating a chelated dienol ester intermediate formed from the non-enolic unsaturated B-keto ester on the surface of the catalyst. However, it should be noted that the rate of catalytic hydrogenation of the B-keto acid of formula Vlll was approximately four times as rapid as was the ease when the corresponding B-keto ester was employed as the reactant. However, hydrogenation of the ester employing approximately three times the amount of catalyst employed in the case of the acid under identical reaction conditions resulted in an approximately equal hydrogenation rate.

The B-keto aldehydes of formula lV-b can be prepared from the acid halides of formula lV-e in accordance with Step (6) of Reaction Scheme A employing a reducing agent such as, lithium aluminum triter' tiarybutoxyhydride. The reaction can be carried out in 12 an inert aprotic organic solvent such as. ethers, e.g.. tetrahydrofuran and hydrocarbons, e.g., toluene and hexane at a temperature range of -l0C. to 60C., preferably between the temperature range of 20C. and 40C. When the reaction is carried out within the aforesaid defined temperature ranges, selective reduction of the acid halide can be effected without attacking the free keto group on the 5-position of the indane of formula lV-e. An alternative method of transforming the acid halide to the corresponding aldehydes can be accomplished by the catalytic hydrogenation of the acid chloride by the Rosenmund Reaction. The technique introduced by Rosenmund consists in adding a small amount of a poisoning agent containing sulfur to the hydrogen catalyst system.

The indanones of formula [V-c wherein R.,, Z and m are as defined as aforesaid can be conveniently prepared in accordance with Steps (8), (9) and (10) of Reaction Scheme A depending upon the nature of X, from the esters of formula IV-d, the acid halides of formula IV-e or the aldehydes of formula IV-b.

Suitable requirements for the leaving group as defined by X in the compounds of formula lV-c are that it should function efficaciously in this process aspect, that is, that it be a suitable leaving group for the process of the present invention. Suitable groups which may be employed to form leaving groups are lower alkyl-aryl sulfonyloxy groups such as, for example, tosyloxy; arylsulfonyloxy groups such as, for example, benzene sulfonyloxy', lower alkyl sulfonyloxy groups such as, for example, mesyloxy (methane sulfonyl); lower alkyl sulfinyloxy; halogen; an acyloxy radical derived from an organic carboxylic acid having I to 7 carbon atoms such as lower alkanoic acid, e.g., acetic acid and butyric acid; aryl carboxylic acids such as p-phenylbenzoic acid and benzoic acid and cycloalkyl carboxylic acids such as cyclopentyl carboxylic acids. Other suitable leaving groups may be selected from the group consisting of wherein each of R and R is independently selected from the group consisting of lower alkyl, aryl and hydrogen, and R and R when taken together to the nitrogen atom to which they are joined, form a 5- or 6- membered heterocyclic ring structure. Thus, the

amino grouping represents secondary and tertiaryamino radicals. It includes monoalkylamino radicals, such as, for example, methyleneamino and butylamino; dialkylamino radicals such as, for example, dimethylamino and dipropylamino, heterocyclic amino radicals. such as, for example, pyrolidino, piperidino, morpholino and 4-methyl-piperizino. The amino radical at a may also be employed as a leaving group in a modified form by alkylation by known means with a suitable organic ester such as, for example, lower alkyl halide, e.g., methyl chloride or a hydrohalic acid such as, for example, hydrogen chloride to form the corresponding quaternary ammonium salt of the formula N* R,, Y=

wherein R R and Y are as defined aforesaid and R is a cation from the organic ester.

Generally, the preferred leaving groups are tosyloxy and mesyloxy although depending on the steroidal end products being prepared, other leaving groups as exemplified above may be more preferable.

The compounds of formula lV-c wherein the leaving group X is lower alkyl-sulfonyloxy, e.g., mesyloxy or lower alkyl aryl-sulfonyloxy, e.g., tosyloxy may be conveniently prepared from the esters of formula lV-d in accordance with Step (9) of Reaction Scheme A by a reaction sequence which comprises first protecting the S-oxo moiety on the indanone, reducing the ester group to the corresponding 4-hydroxy methylene derivative, removing the protecting group before or after conversion to the desired derivative of formula IV-c. Protection can be effected by converting the free oxo group to a cyclic ketal, e.g., a dioxolane ring system by reaction with a suitable lower alkylenedioxy containing compound, e.g., ethylene glycol or to an open ketal with for example, tri-lower alkyl orthoformates. The free oxo moiety can be regenerated after reduction of the 4- ester compounds of formula lV-d to the corresponding 4-hydroxy methylene compounds. A preferred protecting group is the dimethoxy derivative which can suitably be obtained by etherification with trimethyl orthoformate. The thus protected 4a-ester can be reduced employing for example, a suitable reducing agent such as, diisobutyl aluminum hydride to yield the 4-hydroxy methylene compound of the formula wherein R,, Z and m are as defined aforesaid.

Alternatively, the ester of formula lV-cl in the protected form obtained as described above may be reduced to the alcohol of formula lV-c-l using an alkali metal reducing agent such as sodium metal and lower alcohol or lithium aluminum hydride. Compounds of formula lVc wherein the leaving group X is lower alkyl sulfonyloxy or lower alkyl-arylsulfonyloxy can be prepared by esterification with an organic sulfonylhalide such as, for example, toluenesulfonyl halide. especially. p-toluenesulfonyl chloride to prepare the tosyloxy dcrivative or lower alkyl sulfonyl halides, especially meth ane sulfonyl chloride to prepare the mesyloxy derivative. The above reactions can be suitably conducted at a temperature range of l()C to +l0C in the presence of an organic base such as, for example, pyridine by methods known in the art, The corresponding sulfonic acids may also suitably be employed to effect the esterification in lieu of the sulfonyl halide. Leaving groups wherein X is lower alkyl sulfinyloxy may be obtained in an analogous manner to that above by employing the corresponding sulfinyl halides.

Leaving groups wherein X is defined by the grouping wherein R and R are defined as aforesaid can be conveniently obtained from the acid halides of formula lV-e in accordance with process route l0) of Reaction Scheme A by a reaction sequence which comprises the steps of (a) reacting the compounds of formula lV-e with a primary or secondary aliphatic or aromatic amine of the formula by known means to form the corresponding amide of the formula (CH2 )m IV-C-2 I ll wherein R Z. m and R and R are as defined afore said; (b) protecting the 5-oxo group of the compounds of formula lV-c-2 by forming the S-ketal analog in a manner similar to that previously described; (c) reducing the amide with a suitable reducing agent such as, for example, diborane or lithium aluminum hydride in an ether solvent such as, for example, tetrahydrofuran which upon removal of the protecting group by means of dilute mineral acid yields a compound of the formula:

IV-c-3 wherein R Z, m, R and R are as defined aforesaid. The compounds of formula lV-c-3 can be converted to their quaternary salt adducts by alkylation with for example, a lower alkyl halide such as methyl chloride.

Leaving groups wherein X is defined by the grouping wherein at least either R and R is hydrogen, may also be prepared from the aldehydes of formula lV-b in accordance with process route (8) of Reaction Scheme A by selective condensation with a primary amine of the formula -H NR to form by known means the novel imino Shiff Base intermediate of the formula CH 'NR wherein R Z, m and R are as defined aforesaid.

The ald-imines of formula lV-c-4 can be conveniently reduced with hydrogen and Raney Nickel to the desired secondary amines.

Leaving groups wherein X is defined as halogen may be conveniently obtained from the alcohols of formula lV-c-l by reaction with for example, hydrogen halides, e.g., hydrogen chloride, phosphorous halides or thionyl chloride by means known in the art. Leaving groups wherein X is acyloxy as defined aforesaid may be suitably obtained from the compounds of formula lV-c-l by reaction with the desired organic carboxylic acid in the presence of a mineral acid such as sulfuric acid or hydrochloric acid at reflux temperature by means known in the art.

In another aspect, the process of this invention relates to the preparation of compounds of the formulae I, ll and III by reaction of a B-keto ester or ether analog of formula V with compounds of formulae lV-c and lV-a in accordance with Reaction Scheme B. It should be appreciated that compounds of the formulae lV-a and lV-c can be used interchangeably in all of the hereinafter process reactions.

The process of this invention in this aspect, comprises employing the bicyclic indanone derivatives of formulae IV-a and IV-c prepared as aforesaid and reacting them with certain subgeneric compounds encompassed by generic compounds of the formula V-b in accordance with process route (ll) of Reaction Scheme B to prepare the benze[e]indene compounds of formula I. Alternatively, for other subgeneric com pounds encompassed by generic formula V-a in accordance with process routes (12) and (I3) of Reaction Scheme B, the steroids of formulae II and Ill may be prepared. Thus, for certain compounds subgeneric to formula V, viz formula V-b as defined below, the tricyclic benz[ e]indenes of formula I may be prepared by means of the building in an annulation reaction steroidal ring B. Alternatively, for certain other compounds subgeneric to formula V a as defined hereinafter, the steroids of formulae II and "I may be prepared by building by means of compounds of formula V-a, steroidal rings A and B. Thus, the keto compounds of formula V are employed as one of the starting reactants for the preparation of the tricyclic compounds of the formula I or the tetracyclic compounds of formulae II and III. However, it will be appreciated that the length of the carbon chain varies as exemplified by formulae V 11 and V-b below, depending on which class of end products are sought to be prepared. Thus, the B-keto esters and analogs thereof of formula V-a below, are employed wherein it is desired to prepare the tetracyclic steroids of formulae II and III.

wherein R R B, R and R are defined as aforesaid. The B-keto esters and other analogs of formula V-a e5 from the hexanoic esters of formula X via process route (a) by reaction with base, preferably, lithium hydroxide in a lower alcohol solvent, e.g., ethyl alcohol at the reflux temperature of the solvent to form the salt of the acid by saponification ofthe ester. Subsequent reaction of the thus obtained salt with equimolar quantity of an organo metallic compound, preferably, methyl lithium in tetrahydrofuran in the presence of a minute amount of triphenylmethane yields the compounds of formula XII. In effecting the conversion, R should be in a protected keto form, e.g., ketal, the conversion to which has been herein before described. Alternatively, the compounds of formula XII can be prepared in accordance with Reaction Scheme C, via process routes (b) and (c) by reacting the compounds of formula X with a lower alkyl sulfinyl methylene compound, e.g., methyl sulfinyl carbonion [cf., E. 1. Corey and M. Chayltovsky, J. Am. Chem. Soc. 86, I639 I964)] to yield intermediates of formula XI. The compounds of formula XI can if desired, be oxidized to the sulfonyl derivatives with an oxidizing agent such as, for example. potassium permanganate. Reduction of the thus obtained sulfoxides of formula XI with a reducing agent, preferably, aluminum amalgam, yields compounds of formula XII. The compounds of formula XII can be converted to the B-keto esters of formula V-a-l via a Claisen condensation with a carbonate of the formula i slz a wherein R is aryl or lower alkyl in accordance with process route (e). The preferred condensing agent is sodium hydride although alkali lower alkoxides, e.g., sodium alkoxide may also be suitably employed. The reaction is conveniently conducted in an ether solvent such as, for example, diethylether or tetrahydrofuran, the former being preferred at the re flux temperature of the solvent.

REACTION SCHEME C Reduction s lz a tel Z XII CO R steroids of formulae ll or lll include 6-(2-methyl-l,3- dioxolan-2-yl)-3-oxohexanoic acid ethyl ester; 642- ethyl-l ,3-dioxolan-2-yl)-3-oxohexanoic acid ethyl es ter; 3,7-dioxo-octanoic acid methyl ester; 6-( 2-methyl- 1,3-dioxolan-2-yl)-3-oxohexanoic acid propyl ester; 3,7-dioxodecanoic acid ethyl ester; l-methylsulfinyl-S- (Z-methyll ,3dioxolan-2-yl)-2-pentanone and the like. By referring to the general formula IV, it can be thus appreciated that when it is desired to prepare the steroids of formula XVll, the selections of the variables of formula V should be as follows: R is l l is CCHIH--CH,-;

and R R26, R and B are defined aforesaid.

The B-keto esters and other analogs of formula Vb below, are employed wherein it is desired to prepare the tricyclic compounds of formula I butyro acetate, butyro acetonitrile, acetoacetonitrile, l-methyl-sulfinyl-Z-butanone and l-methyl-sulfonyl-Z- pentanone.

While certain groups exemplified by the definition of the term B have been illustrated in the fi-keto ester and other analogs of formulae V-a and V-b, it is to be understood that any other equivalent electron withdrawing group or groups of electrophilic nature can function as well. All that is required for the B segments of the molecule for the process of the reaction of the compounds of formula [V with the compounds of formula V is that it function efficaciously in this process aspect, that is, that it be a suitable electron withdrawing group so as to activate the hydrogen atom on the methylene group next adjacent to the carbonyl group. Preferred electron withdrawing groups are the alkoxy carbonyl esters, especially ethoxy carbonyl. The fi-keto nitriles, e.g., aceto-acetonitrile of formula lV-b may be prepared by reaction of acetonitrile phenyllithium and diethylamine at a temperature range of l0C to +IOC and hydrolyzing in dilute acid the thus obtained imine intermediate to the desired product [ef., Ann. 504, 94 1933)]. The compounds of formula V-a and V-b wherein B is defined as lower alkyl sulfinyl methylene and lower alkyl sulfonyl methylene can be readily prepared from the esters of formula V-a-l in a similar manner to that employed in process step (b) of Reaction Scheme C.

In a further aspect, the synthesis of the present invention relates to the preparation of steroids of the formulae ll and III in accordance with Reaction Scheme B by means of reacting a carbon chain of the formula V-a with a bicyclic compound of the formulae IV-a or lV-c. In reaction Scheme D, the numbers are assigned to Roman numerals for identification. schematically, the sequence of reactions involved in the synthesis of a specific embodiment, namely, l9-nortestosterone is illustrated.

In the Michael addition, process step (a) of Reaction Scheme D, the precursors to the steroidal A and B rings are built up in a single annulation reaction. The reaction is conducted in the presence of a base sufficiently strong to form the anion of the B-keto ester. Exemplary bases are for example, alkali metal lower alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium tertiary butoxide and the like; alkali metal hydroxides such as sodium hydroxide and the like; alkali metal hydrides such as sodium hydride, lithium hydride and the like; alkali metal amides such as lithium amide, sodium amide and the like; methyl sulfinyl carbanion (i.e., the anion from dimethyl sulfoxide). Especially preferred are the alkali metal lower alkoxides. The reaction can be conducted at a temperature range of from about 5C to about 100C. However, it is especially advantageous to conduct a reaction within a temperature range of from 0C to 25C. Moreover, the reaction is suitably conducted in the absence of oxygen for example, in an atmosphere of inert gas such as nitrogen or argon. It is convenient to conduct the reaction in the presence of an organic solvent inert to the reactants as well as the intermediates of formula XVl. Such solvents are for example, dimethylformamide, dimethylsulfoxide and aromatic hydrocarbons, such as, for example, benzene, toluene and xylene. Other suitable solvents include the ethers such as diethvlether. tetrahvdrofuran and the like and lower alkanols such as methanol, ethanol and the like. The concentration of reactants is not critical but it is preferred to use a l:1 molar ratio of reactants of formulae lV-a-l and V-a-3. One may add the reactant of formula V-a-3 to a reaction mixture already containing the bicyclic indanone of formula lV-a-l. However, the reaction can also be effected by placing all the reactants substantially together or preferentially the reactants of formula lV-a-l can be added to a mixture containing the reactants of formula V-a-3. When employing as a starting reactant, the compounds of formula lV-a in lieu of the reactants of formula IV-c-l, the same process conditions are employed and products obtained although the reaction does not necessarily have to proceed by way of a Michael addition mechanism. The sidechain of the reaction intermediate XVI assumes the thermodynamically favorable equatorial configuration under the equilibrating reaction conditions. The alpha orientation of the sidechain is extremely important for the construction of ring B with the proper stereochemistryv No ring closure occurred at this stage because of the preferred enolization of the keto group towards the ester function. Following the Michael addition of the B-keto ester of formula V-a-3 to the bicyelic CID-transindanone of formula lV-b-l, the thus obtained com pound of formula XVI is saponified to remove the ester and cyclized in accordance with process step (b) of Re action Scheme D. The cyclization should be effected under reaction conditions which do not cleave the eyelid ketal protecting group. Exemplary basic cyclization reagents are for example, a dilute aqueous solution of alkali or alkaline metal hydroxides such as for example, sodium hydroxide, lithium hydroxide, calcium hydroxide and the like. The cyclization is suitably conducted in an inert organic solvent such as for example, hydrocarbons, e.g., benzene, toluene and ethers, e.g., tetrahydrofuran. The cyclization can be conducted at room temperature or above room temperature but as a matter of convenience, it is preferable to conduct the reaction at about room temperature. The ester group of the bicyclic intermediate of formula XVI can be removed by saponification of the ester in accordance with Step (b) of Reaction Scheme D to afford the corresponding acid of the formula XVII (after acidification) and decarboxylation to compounds of the formula XVII-l for example, in refluxing toluene under an inert atmosphere such as for example, nitrogen in accordance with Step (c) of Reaction Scheme D. For other cases wherein the electron withdrawing group of formula V (B) is other than ester, e.g., for example, lower alkyl sulfmyl methylene or lower alkyl sulfonyl methylene, the removal of the grouping can be effected by reduction with a reducing agent such as, for example, aluminum amalgam. For cases wherein the electron withdrawing group is nitrile, the reaction can be suitably conducted in an analogous manner to that wherein the electron withdrawing group is an ester as discussed above.

The hydrogenation of the A -double bond of the compounds of formula XVII-a to the compounds of formula XVllI can be effected in accordance with Step (d) of Reaction Scheme D in a lower alcohol solvent such as, for example, ethyl alcohol in the presence of a base, preferably, triethylamine. l9-Nortestosterone can be obtained from the compounds of formula XVlll by hydrolysis of the tertiarybutyl ether cyclization by refluxing in a mineral acid such as, hydrochloric acid or sulfuric acid in a lower alkanol solvent such as methanol in accordance with Step (e) of Reaction Scheme D.

lt should be noted that the process steps exemplified in Reaction Scheme D can be utilized to prepare norgestrel. This can be effected by preparing the 7aB- ethyl analogs of formula lV-a-l as described on page 9 of the instant specification employing the reaction steps (a), (b), (c), (d) and (e) of Reaction Scheme D followed by oxidation utilizing for example, Jones Reagent and ethinylation in accordance with procedures described on page 49 of the instant application. It will be further appreciated that by employing the optically active 7aB-ethylenantiomer of formula lV-a-l of Reaction Scheme D, one can prepare optically active norgestrel.

It will be appreciated that this aspect of the process of the invention for the synthesis of steroids of the formula [I of which l9-nortestosterone is a specific exemplar as set forth in Reaction Scheme D, can be modified so as to yield other pharmaceutically valuable steroids of formula ll, well known in the art, wherein R is other than hydrogen, e.g.. lower alkyl by selectively alkylating the A -compounds of formula XVll-l with a lower alkyl halide in the presence ofa strong base, preferably lithium in liquid ammonia at temperatures in the order of 40C in an inert solvent such as, for example, diethyl ether by means known in the art.

Moreover, when R of the B-keto ester or other analogs thereof of the formula lV-a is oxo and not in a protected ketal form, A, A -steroids of formula III in lieu of the steroids of formula ll will be produced in accordance with Reaction Scheme E. Thus, in a specific embodiment exemplified in Reaction Scheme E, steroids encompassed by the genus of the formula III are prepared. The dione ester of the formula V-a-4 is reacted with the methylene ketal of formula lV-a-l in accordance with Step (a) in the presence of an alkali alk oxide such as 01 N sodium methoxide in a methanol solvent using a temperature range of OC20C to yield the substituted trione of formula XVl-a. The compound of formula XVII-a in accordance with Step (h) of Reaction Scheme E can be hydrolyzed and ring closed using a hydrogen halide acid such as hydrogen bromide in an acetone solvent at a temperature of approximately 20C to yield the acid compound XVII-a. Decarboxylation of compound XVII-a in refluxing tolu ene in accordance with Step (c) yields compound XVII- l -a. The diene steroids of the formula lll-a can be ml I II E in W I N u m 2 8 O N I u obtained in accordance with Step (d) of Reaction Scheme E by cyclizing the compound of formula XVII- l-a using an alkali alkoxide preferably potassium tbutoxide in benzene The l7-hydroxy diene steroids of formula lll-b are obtained in accordance with Step (e) of Reaction Scheme E by refluxing in methanol in the presence of acid, preferably hydrogen chloride.

u l H l m l I 7 N 0 ll: U

0 E U PA: I; H C H 2 X3 0 0 I 9 H H l 1 K v 0 I D ll:

1 H A H H U i v 1 =5 3 H i "I: E,

ill:

The keto compound XVII-l of Reaction Scheme D can also be converted to steroids of the formula XVII- l-a via mild hydrolysis of the ketal moiety employing 0.l N hydrochloric acid in a solvent such as tetrahydrofuran at a temperature of approximately 20C in accordance with Step (f) of Reaction Scheme E. Steroids of Formula [II can be converted to pharmaceutically valuable estrogens by known means (cf. Velluz et al., Angewandte Chemie 72, 725 (I960).

In a further aspect, the present invention relates to the preparation of A, A -steroids of the formula lll by reacting a vinylogous beta keto ester or other analogs of the formula wherein B is defined as aforesaid with compounds of the formula IV-a and IV-c.

A preferred value of B is lower alkoxy carbonyl. Especially preferred is methoxy carbonyl and ethoxy carbonyl. Thus, in a specific embodiment exemplified in Reaction Scheme F, diene steroids of the formula III-b are prepared. The vinylogous beta keto ester of formula Vl-a is reacted with the methylene ketone of formula IV-a-l in accordance with Step (a) of Reaction Scheme F in the presence of an alkali lower alkoxide, preferably 0.1 N sodium methoxide in a lower alcohol solvent, preferably, methanol or ethanol, at a temperature range of C to C yielding the dione of formula XXIII. The diene steroid of formula III-b can be conveniently obtained from the compound of formula XXlIl by cyclization using refluxing mineral acid, preferably, l-N-hydrochloric acid in a lower alcohol solvent, preferably methanol.

In still another aspect of this invention, compounds of the formula lV-f, in Reaction Scheme A, can be converted to compounds of the formula XXIII below, which are subgeneric to the compounds of formula IV Helm XXIII wherein R Z and m are as defined aforesaid by decarboxylation in a refluxing solvent such as, for example, tetrahydrofuran or toluene with or without a strong mineral acid, e.g., hydrochloric acid. The novel C/D-trans bicyclic indanone of compounds of formula XXlll are themselves useful intermediates in a total steroidal synthesis by employing, e.g. the methods described by R. E. Ireland and M. Chaykovsky, J. Org. Chem. 28, 748 (1963) the compounds of formula XXII] can be converted to their A acid analogs by a bromination-dehydrobromination procedure. The A -CID trans indanones can be converted by methods described in the above cited reference to the tricyclic compounds of the formula l which in turn can be converted to pharmaceutically valuable steroids by procedures hereinafter described.

In a further aspect, the synthesis of the present invention relates in accordance with Step (1 l) of Reaction Scheme B to the preparation of 2,3,3a,4,5,7,8,9,9a,9bdecahydro-3a-alkyl-7-o xolI-I-benz[ e ]indenes and 4,4a[3,4ba,5,6,7,8,8a,9, lO-decahydro-8aB-alkyl-3H- phenanthrene-3-ones which contain in the 3-position and 8-position, respectively, an oxo substituent or a REACTION SCI-113M331 F -t-buty1 02 02H; if

IV-a

O-t-butyl {3-OR moiety wherein R has the meaning given in the text accompanying formula I. Many members of this class of known compounds which are valuable intermediates in the synthesis of steroids, for example, benz[e' ]indene derivatives contain asymmetric centers at positions-9a,9b,3a and also at the 3-position if the substitu ent thereat is other than oxo. Thus, of the 3-oxo compounds, there are eight possible different stereoisomers, whereas of the compounds containing a 3-OR substituent, there are possible sixteen stereoisomers.

In a preferred embodiment of this aspect, the synthesis relates to the preparation of the 9a,8,9ba,3a/3- stereoisomers of the benz[e]indene series, its optical antipode and racemate thereof and in the case where the 3-substituent is other than oxo, the 9aB,9ba,- 3aB,3B-stereoisomer its optical antipode and the racemate thereof. The corresponding phenanthrene- 2-ones, i.e., 4a{3,4ba,8aBstereoisomers may also be prepared. The especially desired end-products of the synthesis of this invention are the ()-enantiomers of the formula wherein R R.,, Z and m are as defined aforesaid.

The compounds of formula I can be obtained by commencing the synthesis of this invention with an optically pure starting material of formula IV or by commencing the synthesis of this invention with a racemic (i.e., d1) starting material of the formula IV and effecting resolution of any intermediate stage or after the desired end-product of formula I has been obtained as the racemate.

CTION SCIETT'IE O-t-buty l IV-c-l CH3CH CoCHzC0gC2H5 I g l Referring to Reaction Scheme G, wherein the compounds are assigned Roman numerals for identification schematically, the sequence of reactions involved in the synthesis of a specific embodiment, namely, the benz[e]indenes of formula l-a are illustrated. Thus, ethylpropionylacetate is reacted with a compound of formula lV-c-l wherein the leaving group X exemplified is mesyloxy (compounds of formula lV-a-l can also suitably be employed) to yield compounds of formula XV in accordance with Step (a). Reaction conditions employed for this conversion are identical with that exemplified hereinabove in process step (a) of Reaction Scheme E for the preparation of compound XVI. Compound of formula l-a is obtained in accordance with process step (b) via cyclization which includes an internal aldol condensation and dehydration using a strong mineral acid, e.g., 2N-hydrochloric acid in a lower alcohol solvent, e.g., methanol, at the reflux temperature of the solvent. The conversion of compounds of the formula XV of Reaction Scheme G to compounds of the formula l-a can also be conducted under reaction conditions employed in Steps (b), (c) and (e) of Reaction Scheme D.

As indicated above, the 2,3,3a,4,5,7,8,9,9afi,9badecahydro-3afi-alkyl-7-oxo- 1 H-benz[ e indenes and the 4,4aB,4ba,5,6,7,8- ,8a,9, l O-decahydro-8aB-alkyl-3H-phenanthren-Z-ones of formula I obtained by the process of this invention are useful as intermediates in the formation of the tetracyclic steroid nucleus in accordance with Reaction Scheme F. The benz[e]indenes and the phenanthren- 2-ones are a known class of compounds The benz[e- ]indenes, for example, can be converted into the tetracyclic steroid nucleus by condensing the 7-oxo-benz[e- ]indene with for example, methyl-vinyl ketone or 1,3- dichloro-lbutene according to methods known per se. The patent literature contains many references which are illustrative of methods to effect conversion of the tricyclics of formula I to known steroids of which US. Pat. Nos. 3,115,507; 3,120,544; 3,128,591; 3,150,152 and 3,168,530 are exemplary.

r; Preparation of'ime EficE'EI'Ic Compounds of Formula I -t-buty1.

I l l n xv OgCzHs The ultimate utility of the tricyclic intermediates depends on the nature of R and R For example, compounds wherein R is hydrogen may lead to either 19- nor steroids (Velluz et al., Angewandte Chemie 72, 725, (1960); or alternatively to l0a-l9-nor-steroids (French Pat. No 1,360.55) depending upon the reaction conditions. Further the tricyclics wherein R is hydrogen may be converted into l9-nor-retro(9)3,l0a)- steroids (Velluz et al., Tetrahedron Suppl. 8, Part II, 495 1966) and estrogens, viz compounds having an aromatic A ring e.g., estradiol (Velluz et al., Angewandte Chemie 72, 725 (1960). On the other hand, compounds wherein R is alkyl may lead to compounds of the 9a,10a-series (Velluz et a1., Angewandte Chemie 77, 185, (1960) or alternatively to compounds of the retrosteroid series viz those having inverted centers of asymmetry at positions C and C i.e., the 95,1001 -steroids (Belgium Pat. No. 663,193). Compounds wherein R is lower alkyl may be obtained wherein R of the compounds of formula V-b is lower alkyl (other than methyl).

As illustrated by the following Reaction Scheme H. in the first step of this reaction, the cycle-olefin I may be hydrogenated to the tricyclic compound XIX. The reaction is preferably effected with a noble metal catalyst, e.g., a palladium-charcoal or a lower-rhodium charcoal catalyst. In formula XIX, R represents hydrogen or lower alkyl. Thus, compounds of formula I wherein R represents hydrogen or alkyl can be hydrogenated to the compounds of formula XIX. The conversion of compounds of formula I to compounds of formula XIX and of the latter to compounds of formula XXII are described in greater detail in Belgium Pat. No.

Tricyclic compounds of fonnula I for values wherein R, is hydrogen may be converted by means known in the art to compounds of formula XXI wherein R is hydrogen viz steroids of the l9-nor-l0a-series. Further, the tricyclic compounds of formula I wherein R, is hydrogen may be alternatively converted to compounds of formula II viz the normal steroids of the 9a,l0B-(normal-l9-nor series). This is described more fully in Angewandte Chemie 77, 185 (I965), Velluz, Valls and Nomine and Angewandte Chemie 72, 725 1960), Velluz et al.

REACT ION SCHEME H "Normal steroids XXI "loo-Series" steroids A preferred procedure for converting tricyclic compounds of formula I wherein R is hydrogen to normal steroids of the 9a-l9-nor series of formula I] can be effected by reacting the tricyclic compounds with 4-halo- Z-alkoxy butane wherein the halogen is preferably se lected from the group consisting of chlorine, bromine or iodine. For example, a tricyclic compound of formula i such as 2,3,3a,4,5,7,8,9aB,9ba-decahydro-3afiethyl-3-oxo-7-oxo-lH-benz[e]indene may be reacted with for example, 4-chloro-2tertiarybutoxy-butane in a suitable solvent such as, for example, dimethylformamide or dimethylsulfoxide under a nitrogen atmosphere in the presence of a base such as, for example, sodium hydride or potassium tertiarybutoxide at a temperature range of between and 100 to yield the intermediate l0-[ 3-tertiarybutoxy-butyl1- l 3-ethyll 9' nor-desA-androst-9-ene-5,17-dione. This latter compound can be converted to norgestrel by procedures described more fully in U.S. Pat. application of Gabriel Saucy, Ser. No. 679,989, filed on Nov. 2, 1967.

4-Halo 2-tertiarybutoxy may be prepared from 4- halo-2-butanol by reaction of the latter compound with isobutylene in the presence of a mineral acid such as sulfuric acid or hydrochloric acid at room temperature.

The tricyclic compounds of formula I for values wherein R, is alkyl may be converted by methods known in the art to compounds of formula XXII viz steroids of the retro series via catalytic hydrogenation compounds of the formula XlX and base catalyzed reaction with for example, methyl vinyl ketone.

Compounds of formula l can also be directly reacted with for example. methyl vinyl ketone yielding a 5- hydroxytetracyclic compound of formula XX. These latter compounds can then be subjected to dehydration followed by hydrogenation or to hydrogenation folloxtcd in dehydration to yield a 9,8,lUrror 1001 XXII "Rat r0" steroids steroids of formulae XXI and XXII. These procedures are described in greater detail in Netherlands Octrooiaanvrage No. 6,412,939. Still other methods of utilizing compounds of formula I are described in the literature or in the patents.

Compounds of formula I when converted into compounds of formula II wherein R is ethyl and R, is hydrogen and Z is carbonyl can be selectively alkynylated by a suitable organic metallic acetylide affording norgestrel l3B-eth yll 7a-ethinyll7-hydroxy-gon- 4-ene-3-one). The latter compound can also be prepared according to Reaction Scheme D (cf. Page 39 herein). Exemplary of the suitable alkynylating agents to effect conversion to norgestrel are the alkali acetylides such as lithium acetylide, potassium acetylide, so dium acetylide, etc. The reaction is carried out in the presence of liquid ammonia in suitable solvent systems such as benzene or toluene. The alkynylation is effected preferably at the reflux temperature of the reaction medium although temperatures from to 30 are suitable. Exemplary of other suitable reagents to effect the acetylenic addition are ethylaminediamine complex in dimethylformamide solvent and Grignard analogs such as mono and bis acetylene-magnesium halides by means known in the art.

Further, the l9-nor-compounds of formula ll, wherein R, is propyl are ovulatory inhibitors (cf., Tetrahedron Letters 127 (1961 Velluz, Nomine et al.). Additionally, compounds of formula I wherein R is methyl and R is hydrogen have been converted to the series of formula II, specifically, l9-nortestosterone acetate. J. Org. Chem., 26, 3904 (l96l L. .l. Chinn and H. L. Dryden.

Moreover. compounds of formula I wherein R. is ethyl and R, is methyl and m is equal to 2 can be converted to compounds of formula XXll. i.e., lit-homoretrostcroids. specifically the :tcetyl derivatives of the 37 pregnane series. which are progestational agents and are thus useful in the treatment of fertility disorders. The l8-homo-retroandrostanes of this series have both anti-estrogenic and anti-androgenic activity effecting the secretion of gonadotropic hormones. Hence, these compounds can be used for example, in the treatment of gynecological disorders and as contraceptive agents.

The methods of this invention, as indicated above, result in the preparation either of the desired optical enantiomer illustrated by formulae l and ll or the race mate thereof. The optical antipode illustrated by formulae l and II can be obtained either by resolution of the corresponding racemic end product or by resolution of racemic starting material or, if racemic starting material is directly subjected to the methods of this invention, resolution of any intermediate racemate. The present invention provides a facile synthesis for optically active end products as a result of the fact that optical specificity is preserved throughout the synthesis as a result of the stereo selectivity of the individual process conversions exemplified in Reaction Schemes A, B, C, D, E and F. Resolution can be effected by conventional resolution means known per se. For example, compounds in which the moiety represented by the symbol 2 is hydroxy-methylene, or a group convertible into hydroxymethylene such as carbonyl (convertible by reduction to hydroxymethylene) or an ether or ester of hydroxy'methylene (convertible by hydrolysis to bydroxy-methylene), can be resolved by reacting the compound containing the hydroxy-methylene moiety with a dibasic acid to form a half-acid ester. If the dibasic acids are, for example, dibasic-lower alkanoic acids such as oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid or the like, or an aromatic dibasic acid such as phthalic acid, the so-formed half-acid ester is then reacted to form a salt with an optically active base such as brucine, ephedrine or quinine and the resulting diastereoisomeric products are separated. Alternatively, the hydroxy-methylene moiety can be esterified with an optically active acid such as camphorsulfonic acid and the resulting diastereoisomeric esters can be separated. The optical antipodes can be regenerated from the separated diastereoisomeric salts and esters by conventional means.

The following examples are illustrative but not limitative of the invention. All temperatures are stated in degrees Centigrade. Infrared, ultraviolet and nuclear magnetic resonance spectra where taken were consistent with stated structures. IR spectra where indicated were taken in chloroform. UV spectra where indicated were taken in ethyl alcohol.

EXAM PLE l A 0.5 weight per cent solution of lB-tertiarybutoxy- 5,6,7, 7a-tetrahydro-7a/3-methyl-5-oxo-indane in absolute ethanol was hydrogenated at atmospheric pressure and room temperature using a ten per cent palladium/- CaCO catalyst. Hydrogenation was stopped after the uptake of 1 mole of hydrogen. The solution was then filtered and evaporated in vacuo to give a crude hydrogenation product. This crude product was then subjected to hydrolysis by stirring and refluxing for six hours with a 1:1 mixture of tetrahydrofuran and 2 N hydrochloric acid under a nitrogen atmosphere. The solu tion was then cooled by means of an ice bath and neutralized with 5 N sodium hydroxide. The solvent was then evaporated in vacuo and the residue was extracted sequentially with ethyl acetate and then ether. The extract was washed with a saturated sodium chloride solution and then dried over sodium sulfate. Evaporation of the solvent in vacuo afforded a mixture of cis and trans reduction products 3aB,4.7,7a-tetrahydro-1B- hydroxy-7aB-methyl-5(oHlindanonc and 3aa,4,7,7atetrahydrol B -hydroxy-7aB-methyl-5( 6H )indanone which was analyzed by vapor phase chromatography and NMR. The vapor phase chromatography consisting of repeatedly subjecting the crude mixture of 3aB.4.7- ,7a-tetrahydrol B-hydroxy-7aB-methyl-5( 6H )indanone and 3aa,4,7,7a-tetrahydro-lB-hydroxy-7a/3- methyl-5(6H)indanone to vapor phase chromatography in 40 milligram portions on a BarberColeman Model 5072 equipped with flame detection and a split ratio of 5:95. By this technique, 3aa,4,7,7a-tetrahydrolB-hydroxy-7aB-methyl-5(6H)indanone was obtained as an oil. 'y 3620, 3300-3550 and l7l5 cm in the infrared spectrum.

EXAMPLE 2 1 l0 Mg. of purified trans alcohol 3aa,4,7,7a-tetrahydro-1B-hydroxy-3aB-methyl-5(6H)indanone was oxidized by reacting with 0.175 ml. of 8 N chromium trioxide in sulfuric acid in a medium of 5 ml. of acetone under a nitrogen atmosphere at l0C over approximately a five minute period. The reaction mixture was quenched by the addition of 5.0 ml. of ice water and the organic solvent was removed in vacuo. The aqueous solution was then extracted with a mixture of ethyl acetate and ether. The organic phase was washed with sodium bicarbonate and a saturated sodium chloride solution. The extract was dried over sodium sulfate and evaporated in vacuo to give the crude oxidation product 3aa,4,7.7a-tetrahydro-7aB-methyll ,5-(6H indanedione, as an oil. 68 Mg. of the crude oxidation product, 3aoz,4,7,7a-tetrahydro-7aB-methyl-l ,5- (6H)indanedione was subjected to vapor phase chromatography in 14 mg. aliquots on a Barber-Coleman Model 5072 equipped with flame detection at a split ration of 5:95. Fractionation gave pure 3aoz,4,7,7a-tetrahydro-7-aB-methyl-l,5-(6H)-indanedione. as an oil; 7 1740 and l7l2 cm" in the infrared spectrum. A sample was crystallized from ether-petroleum ether, m.p. 52-53C.

EXAMPLE 3 45 Ml. of dimethylsulfoxide distilled from calcium hydride was added to a 53 per cent dispersion of 1.03 g. of sodium hydride in mineral oil which had been previousiy washed with anhydrous ether and dried under a nitrogen atmosphere. The mixture was stirred at 20C, and a solution of 5.0 grams of lB-tertiarybutoxy- 5,6,7,7atetrahydro-7a/3-methyl-5-oxo-indane in 45 ml. of dimethylsulfoxide was added at once. The reaction mixture was agitated until hydrogen evolution ceased, approximately four hours thereafter. The dimethylsulfoxide was then distilled off under high vacuo utilizing a bath kept at a temperature of C. The residue (conjugate anion of lB-tertiarybutoxy-5,6,7,7a-tetrahydro- 7aB-methyl-5-oxo-indane) was dissolved in ml. of anhydrous ether and added as rapidly as possible (approximately 2 minutes) to a one liter flask containing a thick slurry of anhydrous solid carbon dioxide in 225 ml. of anhydrous ether. The reaction mixture was stirred vigorously. The slurry was formed by cooling 2-3 ml. of anhydrous ether with a dry icemethanol cooling mixture and then permitting anhydrous solid carbon dioxide from an inverted tank of bone dry 

1. A COMPOUND OF THE FORMULA
 2. A compound as in claim 1 wherein Z is CH(OR2); R2 is lower alkyl; R4 is selected from the group consisting of methyl, ethyl and propyl; and m is
 1. 3. 1 Beta -tertiarybutoxy-3a Alpha ,4 Beta ,5,6,7,7a-hexahydro-5,5-dimethoxy-7a Beta -methyl-4 Alpha -indanmethanol.
 4. 1 Beta -tertiarybutoxy-3a Alpha ,5,6,7,7a-hexahydro-7a Beta -methyl-5-oxo-4 Alpha -indanmethanol. 